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Lower CTLA4 Levels May Indicate Risk of MG in Patients With Thymoma

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The findings from among patients with myasthenia gravis (MG) could point the way to a potential new drug target, the authors said.

Scientists have identified a biomarker with potential to help clinicians better understand which patients with thymoma are at the highest risk of developing myasthenia gravis (MG). The study was published in Neurology Neuroimmunology & Neuroinflammation.

The authors explained that thymomas—neoplasms derived from the epithelial cells of the thymus—are commonly associated with MG, an autoimmune disease marked by fatigue and weakness. Ten percent to 15% of people with MG have a thymoma, and 30% to 45% of people with thymomas have MG, Gallardo they said. However, it is not yet clear which patients with thymomas will go on to develop MG.

“The pathophysiologic mechanisms by which autoimmunity is triggered in patients with thymoma-associated MG are believed to differ from those of other MG subtypes;” the authors said. “However, these mechanisms are not completely understood.”

In the new study, the investigators looked closely at cytotoxic T lymphocyte–associated antigen 4 (CTLA4), a CD28 antagonistic homolog receptor expressed by T cells. They noted that CTLA4 interacts with CD80 and CD86 on antigen-presenting cells and acts as an immune checkpoint. It is also involved in regulating self-reactive T-cell generation in the thymus, they said. They added that anti-CTLA4 antibodies, which have been used effectively to treat certain types of cancer, have been associated with the development of autoimmune diseases, including MG.

For these and other reasons, the authors wondered whether CTLA4 levels might be linked with the risk of developing MG in patients with thymoma.

The authors retrospectively analyzed all thymoma patients treated at their hospital between 2010 and 2020, regardless of whether the patient had MG. They found 41 patients, 23 of whom had MG. Ten samples were also taken from patients with healthy thymuses to serve as controls, they said. The authors looked at immunochemistry results to determine the number of CTLA4-positive cells within patients’ thymoma samples, and then looked for links between those results and the patient’s MG status.

The results showed a significant gap between the number of CTLA4-positive cells in people with MG compared to those without: mean of 69.3 cells/mm2 (95% CI, 39.6-99.1) vs 674.4 cells/mm2 (95% CI, 276.0-1024.0; P = .001); the control group had an average of 200.74 cells/mm2 (95% CI, 57.9-343.6; P = .02). However, CTLA4 levels did not appear to be associated with differences in MG outcome or whether or not a patient’s MG was refractory to therapy. The authors also discovered 2 polymorphisms in the CTLA4 genes of some patients, although only one of those polymorphisms—rs231775—was linked with a trend toward a lower CTLA4-positive cell count; the investigators said the association did not reach statistical significance.

The investigators characterized their findings as a starting point; they said it represents one possible path to explore in the investigation of MG and its causes.

“A better understanding of the mechanisms by which autoimmunity is triggered in patients with MG is essential to develop specific therapies designed to minimize or even prevent the frequent side effects of current immunosuppressants,” they noted.

The authors said larger studies will be needed to clarify the associations they identified.

Reference

Álvarez-Velasco R, Dols-Icardo O, El Bounasri S, et al. Reduced number of thymoma ctla4-positive cells is associated with a higher probability of developing myasthenia gravis. Neurol Neuroimmunol Neuroinflamm. 2023;10(2):e200085. doi:10.1212/NXI.0000000000200085

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